This invention covers intermediates and a synthetic route for making 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexanoic acid and its analogs. This acid and its named analogs are selective for inhibiting the catalytic site in the phosphodiesterase isoenzyme denominated IV (PDE IV hereafter) and as such the acids are useful in treating a number of diseases which can be moderated by affecting the PDE IV enzyme and its subtypes.
Bronchial asthma is a complex, multifactorial disease characterized by reversible narrowing of the airway and hyper-reactivity of the respiratory tract to external stimuli.
Identification of novel therapeutic agents for asthma is made difficult by the fact that multiple mediators are responsible for the development of the disease. Thus, it seems unlikely that eliminating the effects of a single mediator will have a substantial effect on all three components of chronic asthma. An alternative to the xe2x80x9cmediator approachxe2x80x9d is to regulate the activity of the cells responsible for the pathophysiology of the disease.
One such way is by elevating levels of cAMP (adenosine cyclic 3xe2x80x2,5xe2x80x2-monophosphate). Cyclic AMP has been shown to be a second messenger mediating the biologic responses to a wide range of hormones, neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4th International Congress Excerpta Medica, 17-29, 1973]. When the appropriate agonist binds to specific cell surface receptors, adenylate cyclase is activated, which converts Mg+2-ATP to cAMP at an accelerated rate.
Cyclic AMP modulates the activity of most, if not all, of the cells that contribute to the pathophysiology of extrinsic (allergic) asthma. As such, an elevation of cAMP would produce beneficial effects including: 1) airway smooth muscle relaxation, 2) inhibition of mast cell mediator release, 3) suppression of neutrophil degranulation, 4) inhibition of basophil degranulation, and 5) inhibition of monocyte and macrophage activation. Hence, compounds that activate adenylate cyclase or inhibit phosphodiesterase should be effective in suppressing the inappropriate activation of airway smooth muscle and a wide variety of inflammatory cells. The principal cellular mechanism for the inactivation of cAMP is hydrolysis of the 3xe2x80x2-phosphodiester bond by one or more of a family of isozymes referred to as cyclic nucleotide phosphodiesterases (PDEs).
It has now been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. [Torphy, xe2x80x9cPhosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmatic Agentsxe2x80x9d in New Drugs for Asthma, Barnes, ed. IBC Technical Services Ltd., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE IV inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE IV inhibitors would be effective in the asthmatic lung, where levels of prostaglandin E2 and prostacyclin (activators of adenylate cyclase) are elevated. Such compounds would offer a unique approach toward the pharmacotherapy of bronchial asthma and possess significant therapeutic advantages over agents currently on the market.
The process and intermediates of this invention provide a means for making certain 4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids which are useful for treating asthma, and other diseases which can be moderated by affecting the PDE IV enzyme and its subtypes. The final products of particular interest are fully described in U.S. Pat. No. 5,552,483 issues Sep. 3, 1996. The information and representations disclosed therein, in so far are that information and those representations are necessary to the understanding of this invention and in its practice, in total, are incorporated herein by reference.
This invention relates a method for making a compound of formula I 
R1 is xe2x80x94(CR4R5)nC(O)O(CR4R5)mR6, xe2x80x94(CR4R5)nC(O)NR4(CR4R5)mR6, xe2x80x94(CR4R5)nO(CR4R5)mR6, or xe2x80x94(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens;
m is 0 to 2;
n is 1 to 4;
r is 0 to 6;
R4 and R5 are independently selected from hydrogen or a C1-2 alkyl;
R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;
provided that:
a) when R6 is hydroxyl, then m is 2; or
b) when R6 is hydroxyl, then r is 2 to 6; or
c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or
d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;
e) when n is 1 and m is 0, then R6 is other than H in xe2x80x94(CR4R5)nO(CR4R5)mR6;
X is YR2, halogen, nitro, NH2, or formyl amine;
X2 is O or NR8;
Y is O or S(O)mxe2x80x2;
mxe2x80x2 is 0, 1, or 2;
R2 is independently selected from xe2x80x94CH3 or xe2x80x94CH2CH3 optionally substituted by 1 or more halogens;
R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, xe2x80x94CHxe2x95x90CR8xe2x80x2R8xe2x80x2, cyclopropyl optionally substituted by R8xe2x80x2, CN, OR8, CH2OR8, NR8R10, CH2NR8R10, C(Zxe2x80x2)H, C(O)OR8, C(O)NR8R10, or Cxe2x89xa1CR8xe2x80x2;
R8 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines;
R8xe2x80x2 is R8 or fluorine;
R10 is OR8 or R11;
R11 is hydrogen, or C1-4 alkyl optionally substituted by one to three fluorines;
Zxe2x80x2 is O, NR9, NOR8, NCN, C(xe2x80x94CN)2, CR8CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(xe2x80x94CN)NO2, C(xe2x80x94CN)C(O)OR9, or C(xe2x80x94CN)C(O)NR8R8;
Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or xe2x80x94C(O)OH;
which method comprises treating a compound of formula II(a) or II(b) 
xe2x80x83where R1, R3, X2 and X are the same as for formula (I), with lithium bromide or magnesium bromide in a polar solvent at a temperature between about 60xc2x0 and 100xc2x0 C., optionally under an inert atmosphere for a time sufficient for the reaction to go to completion.
This invention also relates to compounds of formula II per se.
In another aspect this invention relates to a one-pot method for making the ketone of formula III starting with isovanillin, 
where R1, R3, X2 and X are the same as for formula (I), as more fully described herein below.
In yet a third aspect this invention relates to a process for preparing a compound of formula I which process comprises treating a compound of formula (IV) using an alkali metal cyanide, for example LiCN, in a compatible solvent such as dimethylformamide which contains a small proportion of water 
where, in formula III, R1, X and X2 are the same as in formula I.
In a further embodiment this invention relates to a process for making a compound of formula I comprising treating an acyl nitrile of formula V with water. 
The X, X2 and R1 groups in formula V are the same as those in formula I.
In yet a further embodiment this invention relates to compounds of formula II 
R1 is xe2x80x94(CR4R5)nC(O)O(CR4R5)mR6, xe2x80x94(CR4R5)nC(O)NR4(CR4R5)mR6, xe2x80x94(CR4R5)nO(CR4R5)mR6, or xe2x80x94(CR4R5)rR6 wherein the alkyl moieties may be optionally substituted with one or more halogens;
m is 0 to 2;
n is 1 to 4;
r is 0 to 6;
R4 and R5 are independently selected from hydrogen or a C1-2 alkyl;
R6 is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC1-3 alkyl, halo substituted aryloxyC1-3 alkyl, indanyl, indenyl, C7-11 polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C3-6 cycloalkyl, or a C4-6 cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group;
provided that:
a) when R6 is hydroxyl, then m is 2; or
b) when R6 is hydroxyl, then r is 2 to 6; or
c) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or
d) when R6 is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;
e) when n is 1 and m is 0, then R6 is other than H in xe2x80x94(CR4R5)nO(CR4R5)mR6;
X is YR2, halogen, nitro, NH2, or formyl amine;
X2 is O or NR8;
Y is O or S(O)mxe2x80x2;
mxe2x80x2 is 0, 1, or 2;
R2 is independently selected from xe2x80x94CH3 or xe2x80x94CH2CH3 optionally substituted by 1 or more halogens;
R3 is hydrogen, halogen, C1-4 alkyl, CH2NHC(O)C(O)NH2, halo-substituted C1-4 alkyl, xe2x80x94CHxe2x95x90CR8xe2x80x2R8xe2x80x2, cyclopropyl optionally substituted by R8xe2x80x2, CN, OR8, CH2OR8, NR8R10, CH2NR8R10, C(Zxe2x80x2)H, C(O)OR8, C(O)NR8R10, or Cxe2x95x90CR8xe2x80x2
R8 is hydrogen or C1-4 alkyl optionally substituted by one to three fluorines;
R8xe2x80x2 is R8 or fluorine;
R10 is OR8 or R11;
R11 is hydrogen, or C1-4 alkyl optionally substituted by one to three fluorines;
Zxe2x80x2 is O, NR9, NOR8, NCN, C(xe2x80x94CN)2, CR8CN, CR8NO2, CR8C(O)OR8, CR8C(O)NR8R8, C(xe2x80x94CN)NO2, C(xe2x80x94CN)C(O)OR9, or C(xe2x80x94CN)C(O)NR8R8, and
T is CN or SO2R where R is C1-6alkyl or C0-3alkylphenyl.
This process involves a nine step synthesis for preparing certain 4-substituted-4-(3,4-disubstitutedphenyl)cyclohexanoic acids. The starting material is isovanillin, 3-hydroxy-4-methoxybenzaldehyde, or an analog thereof. xe2x80x9cAnalogxe2x80x9d means another 3 and/or 4 position substituent conforming to the definitions of R1, R3, X2 and X in the definition of formula (I).
The compounds which are made by this process are PDE IV inhibitors. They are useful for treating a number of diseases as described in U.S. Pat. No. 5,552,438 issued Sep. 3, 1996.
The preferred compounds which can be made by this process are as follows:
Preferred R1 substitutents for the compounds of all named formulas are CH2-cyclopropyl, CH2xe2x80x94C5-6 cycloalkyl, C4-6 cycloalkyl unsubstituted or substituted with OHC7-11 polycycloalkyl, (3- or 4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C1-2 alkyl unsubstituted or substituted by 1 or more fluorines, xe2x80x94(CH2)1-3C(O)O(CH2)0-2CH3, xe2x80x94(CH2)1-3O(CH2)0-2CH3, and xe2x80x94(CH2)2-4OH.
Preferred X groups for Formula (I), (II) or (III) are those wherein X is YR2 and Y is oxygen. The preferred X2 group for Formula (I) is that wherein X2 is oxygen. Preferred R2 groups are a C1-2 alkyl unsubstituted or substituted by 1 or more halogens. The halogen atoms are preferably fluorine and chlorine, more preferably fluorine. More preferred R2 groups are those wherein R2 is methyl, or the fluoro-substituted alkyls, specifically a C1-2 alkyl, such as a xe2x80x94CF3, xe2x80x94CHF2, or xe2x80x94CH2CHF2 moiety. Most preferred are the xe2x80x94CHF2 and xe2x80x94CH3 moieties.
Most preferred are those compounds wherein R1 is xe2x80x94CH2-cyclopropyl, cyclopentyl, 3-hydroxycyclopentyl, methyl or CF2H; X is YR2; Y is oxygen; X2 is oxygen; and R2 is CF2H or methyl; and R3 is CN.
A representative schematic of this process is set out in Scheme I. This graphical representation uses specific examples to illustrate the general methodology used in this invention. 
Referring to Scheme I, isovanillin, 3-hydroxy-4-methoxybenzaldehyde, is a readily available starting material. It can be alkylated with an R1X moiety (X=Cl, Br, and I) as represented by cyclopentyl chloride. The reaction vessel is first flushed with an inert gas, for example nitrogen. A polar solvent such as DMF is then added to the vessel, then the isovanillin, then the R1X adduct, and some base. About 2 equivalents of the R1X adduct versus the isovanillin are used. Likewise about 2 equivalents of base are used, again relative to the isovanillin. The base can be any inorganic base or a carbonate. Here it is illustrated by potassium carbonate. The vessel contents are heated to about 125xc2x0 C. for about 90 to 120 minutes in which time the reaction will have gone to completion. The vessel contents are cooled to ambient temperature, filtered to remove the inorganic salts, and washed with an alcohol such as methanol. This filtrate contains the aldehyde, labeled 1xe2x80x941.
The aldehyde is then reduced to the alcohol using an inorganic reducing agent. To do this the filtrate from the foregoing reaction is treated with sodium borohydride and after workup affords the desired alcohol, 1-2 in 97% overall yield from isovanillin. This is achieved by cooling the filtrate to about 0xc2x0 C. after which a reducing agent, here sodium borohydride, is added. About 0.25 to 0.5 equivalents of this reducing agent is used. The temperature is keep at about 0xc2x0 C. during the addition of the reducing agent and for about 30 to 40 minutes thereafter. Then the temperature is allowed to rise to about room temperature after which about one-half an equivalent of HCl is added to the reaction vessel. The alcohol is then extracted into an organic solvent, toluene is illustrated, and washed with dilute sodium bicarbonate.
The top organic layer containing the alcohol is then treated with excess concentrated hydrochloric acid at ambient temperature to afford, after workup, the desired benzyl chloride 1-3. The chloride is isolated as a w/w solution in an amide solvent, DMF is illustrated, and treated with about a 50% molar excess of sodium cyanide at a mildly elevated temperature, here illustrated as 55xc2x0 C. This affords the desired nitrile 1-4. The nitrile is isolated as a w/w solution in an appropriate solvent such as anhydrous acetonitrile and used directly in the next step.
The nitrile solution is charged with methyl acrylate. It is cooled to about xe2x88x9210xc2x0 C., and slowly treated with a catalytic amount of Triton-B in the same solvent as used to dissolve the nitrile. The methyl acrylate is added in a 3 to 4-fold excess. The reaction is complete within 30 to 45 minutes after which the acrylate addition, the pimelate product, 1-5, is isolated as a w/w solution in toluene and treated with about 2 equivalents of sodium methoxide at about 75xc2x0 C. to give the xcex2-keto-ester product, 1-6. The reaction solution is cooled and neutralized to pH 7 with mineral acid such as 6N hydrochloric acid. The solution is charged with dimethyl sulfoxide, sodium chloride, water, and heated, for example to about 150xc2x0 C., to effect the decarboxylation to give 1-7. The ketone, 1-7, is isolated from the solvent system as an off-white solid.
The dicarbonitrile 1-8 is prepared from the ketone by treating the ketone with chloroacetonitrile in the presence of an inorganic base and a catalytic amount of benzyltriethylammonium chloride (BTEAC). The ketone is charged into a mixture of strong base (aqueous potassium hydroxide) and a water miscible solvent such as tetrahydrofuran. A slight excess of chloroacetonitrile is added at reduced temperature, about 0xc2x0 C. or thereabouts. The reaction is maintained at about that temperature for the duration of the reaction, usually about 1 hour. The product is isolated and usually it is crystalline.
The dicarbonitrile is converted to the cyclohexanecarboxylic acid using a Lewis acid catalyst; water is also needed to drive the reaction to the acid. Without water intermediates 1-10a and 1-10b may dimerize. This reaction is carried out by charging a vessel with solvents, in this instance exemplified by DMF, acetonitrile and water, and the Lewis acid (about 1.5 equivalents), LiBr is illustrated, sweeping the vessel with an inert gas, adding the dicarbonitrile IIa or IIb, or a mixture of IIa and IIb and heating the vessel and its contents to about 100xc2x0 C. for a number of hours, 8 hours being an example. The acid is isolated by conventional means.
It should be noted that this reaction, that is the conversion of the epoxide to the acid, involves several intermediates which do not need to be isolated. It has been found that treating the epoxide with LiBr yields intermediates 1-9a and 1-9b. Intermediate 1-9a is formed when LiBr is added to the reaction pot. But intermediate 1-9a converts back to the epoxide under the recited reaction conditions. Intermediate 1-9b is also formed but apparently reacts rapidly to form intermediates such as enolate A, 1-10a and 1-10b etc leading to product. So it appears 1-9a and 1-9b are formed, but that 1-9a converts back to the epoxide which ultimately forms 1-9b which is then converted to other intermediates enroute to forming the acids of 1-11a and 1-11b. Parenthetically the designation xe2x80x9cOM(H)xe2x80x9d in 1-9a and 1-9b means the metal salt of the alcohol or the alcohol per se, depending on the reaction conditions. Intermediate 1-9b is believed to convert to the acyl nitrites of formulas 1-10a and 1-10b via the proposed bracketed intermediate. The existence of the proposed bracketed intermediate (enolate) has not been fully confirmed. And while the acyl nitrites of 1-10a and 1-10b have not been directly observed, indirect evidence exists for these compounds by virtue of the fact the bis-condensation product dimer B was isolated and is analogous to reported compounds where a similar bis-condensate is the product of an acyl nitrile. 
Dimers such as dimer A are known to form from the likes of acyl nitrites 1-10a/b in the presence of HCN (Thesing, J.; Witzel, D.; Brehm, A. Angew Chem., 1956, 68, 425; and Hunig, S.; Schaller, R. Angew. Chem. Int. Ed. Engl., 1982, 21,36).
And in addition, authentic samples of intermediates 1-10a and 1-10b were prepared and found to convert to acids 1-11a and 1-11b when exposed to water. The equitorial isomer 1-10a converted to the acid in an equitorial/axial ratio of about 98:2 while the axial isomer 1-10a isomerized to a perponderance of the equitorial isomer 1-11a (77:23). It is believed the axial acyl nitrile converts to the equitorial acyl nitrile via the proposed bracketed enolate intermediate.
The second, following reaction scheme illustrates preparing the acids of formula (I) from the bromoaldehyde of formula (IV). 